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CENTER FOR DRUG EVALUATION AND RESEARCH
APPROVAL PACKAGE FOR:
APPLICATION NWlBER
50-783
Pharmacology Review(s)
--_------_ --..-..-__-_I_
NDA 50-783
SEP 25 2000
RXVIKW AND EVALUATION OF PBARMACOLOGY/TOXICOLoGyDATA:
KEY WORDS: Doxycycline; periodontitie
reviewer Name: Norman A. See, Ph.D.
Divieion Name: DDDDP; RFD-540
Review completion Date: IS-SRP-2000
Review number: 001
IND/NDA number: MIA SO=783
Serial nwnber of submieeion: 000
Letter date of oubmi~eion: 31-MAR-2000
Center receipt d8te: OS-APR-2000
Information to oponaor: Yea ( 1 No (X)
Sponsor (or agent) : Collagenex Pharmaceuticals, Inc.
Drug:
Code name: None
Generic mine: Doxycycline Eyclate, USP
Trade name: Periortat tablOtP
Chemical neme: I-(dimethylamino) -1,4,4ar5,5a,6,11,12a-octahydro-
~,9,~Or~2,~2e-p~tahydroxy-6-methyl-l,ll-dioxo-2-naphthaceoscarbox~de
monohydrochloride
as registry number: 17086-28-l
Molecular formula/Molecular: weight: (CpnH~~hO1~HCl~o~CzH~~*&0/1025.89
Structure:
“3C\ OH
Relevant INDe/WDAa/DMPP: INDL-)NDA SO-744
Drug clarm: Antibiotic. However, it is urod as a collagenaee inhibitor at a
cub-antimicrobial level in connection with this application.
Indication: Treatmaat of periodontitie
Clinical formulation: Tablets that contain:
Doxycycline hyclate,
Microcq8tallide cellul0ar, NP
MagnesiU 8tearate,
+Equivalont to 2O.Omg doxycycline
Route of administration: orai
Proposed clinical protocol or use: Two tablet8 per dey (40114 doxycycline per
day, or 0.67mg/kg/day in a 60kg individual: exprenoed am the salt, the douage
is 46xng doxycycline hyclata pot day, or 0.77mg/kg/day). Thr product is
.- ___ _... - -. - ~. --.
.,
d
labeled for up to nine montha of continuous use per treatment episode. The
meximum number of treatment episodea that a given patient may undergo is
unclear, but ia unlikely to be more than three or four (according to the
clinical reviewer).
Previoua clinical experience: Pleaae aee the original pharmacology summary of
NDA 50-744.
Background and product An eeaentially
history: identical product, Perioatat
capsulea, was approved under The aponaor
NDA 50-744. wiahea to be able to
market a tablet formulation and NDA 50-783 waa submitted
of Parioatat, to that
end. The formulations and proposed usage of the two producta are identical,
with the exception that the tablets contain [ ](a film coating
agent) in lieu of n hard gelatin capsule.
Studies reviewed within thia aubmiaaion: None. Please see the Pharmacology
raviewa of MIA SO-744 for evaluation of applicable data.
Studiea not reviewed within thia aubmiaaion: None.
OVRFUGL SUMMARYAND BVALUATION:
Safety Evaluation: The proposed exposure to doxycycline ia identical to that
approved under NDA 50-7441 please see the Pharmacology review8 of NDA 50-744
for evaluation of applicable data. The only difference between the tab1 t and
capsule formulations la that the tableta contain( t (a
film coating agent) in lieu of a hard gelatin capsule. The formulation of
c 1 ia:
Inqrcdient Amount .- 1%. w/w)
-
The daily exposure to theae compoun
(two tablets per day,
Inqredient Daily Rxpoaure (ma)
c
All of the component8 of I \ are liated in
the CDHR Inactive Ingredient Guide aa having been excipienta n drug Droduc a
that we e approved for oral use, aa are other formulationa of t 5
t i is a c onent of many fooda, including dairy producta. 1
T a GRAS aa a direct food additive (21 CPR 172.874).1
I ia liated aa a diluent in color additive mixture8 for drug use (21 CPR
73.1575) . )a GRAS aa a direct food additive (21 CPR 184.1901 and 21
CPR 582.190 \I 1. These expoaurea are acceptable.
Clinical relevance of aafety iaauear None
Other clinically relevant iaauea: None
Conclusiona: The proposed exposure to the drug product is safe.
Conmunication review2
s Labeling review (NDA):
---_--
I ----
-. .
NDA 50-783 3
Labelingx The eubmitted &aft label, which duplicates the currently approved
label for Perioetat capmulem with reepect to the warnings, pregnancy category
and carcinogeneais oectione, is acceptable to thin reviewer.
RBCOMKENDATIONS:
Internal commentmr NDA 50-783 im approvable in regard to pharmacologic and
toxicologic concerns.
External Reconnnendationn (to sponsor): None
Draft letter Content for Sponsor: Nonm
Puture development or NDA issuem: The sponsor hao committed (under NDA 50-744)
to conduct a two-year carcinogeneois bioaeeay with doxycycline hyclate in
rats, and to submit the data when they become available. The most recent
annual report submitted to NDA 50-783 indicated that the in-life phamo of the
bioaeeay had been completed and the report i8 in preparation. When thoeo data
are eubmitted and reviewed, the label8 of NDA 50-744 and NDA 50-783 will ba
updated.
.-
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Table 6
Summary of Bioavailability (BA) Results: Statistics for Pharmacokinetic Parametersby Treatment and Gender
Per Protocol Intent-to-Treat
Parameter Treatment Statistic Males Females Total Males Females Total
AUC O-
inf
F N 9 10 19 9 10 19
Arithmetic Mean 4883 5557 5238 4883 5557 5238
Geometric Mean 4568 5359 4969 4568 5359 4969
Coefficient of Variation (%) 41.5 29.7 34.1 41.5 29.7 34.7
T N 9 10 19 9 11 20
Arithmetic Mean 5671 5984 5836 5671 5949 5824
Geometric Mean 5259 5700 5487 5259 5691 5493
Coefficient of Variation (%) 45.6 32.7 38.0 45.6 31.2 37.1
AUC O-1
F N 9 10 19 9 10 -.--.19
Arithmetic Mean 4055 4392 4232 4055 4392 4232
Geometric Mean 3713 4286 4004 3713 4286 4004
Coefficient of Variation (%) 46.1 23.5 34.4 46.1 23.5 34.4
T N 9 10 19 9 11 20
Arithmetic Mean 5069 5089 5079 5069 5091 SO81
Geometric Mean 4618 4148 4685 4616 4780 4706
Coeffkient of Variation (%) 50.3 38.3 43.0 50.3 36.3 41.9
Cmax
F N 9 10 19 9 10 19
Arithmetic Mean 243.6 297.2 271.8 243.6 297.2 271.8
Geometric Mean 225.8 292.6 258.8 225.8 292.6 258.8
Coefficient of Variation (%) 42.5 19.0 31.1 42.5 19.0 31.1
T N 9 10 19 9 11 20
Arithmetic Mean 308.3 410.0 361.8 308.3 417.2 368.2
Geometric Mean 294.1 403.2 347.2 294. I 410.4 353.2
Coefficient of Variation (%) 33.8 18.0 28.0 33.8 17.7 27.9
tmax
F N 9 10 19 9 10 19
Arithmetic Mean 3.22 3.55 3.39 3.22 3.55 3.39
-_ GeometricMean 2.70 3.33 3.01 2.70 3.33 3.01
Coefficient of Variation (%) 65.9 35.4 49.5 65.9 35.4 49.5
T N 9 10 19 9 11 20
Arithmetic Mean 1.33 1.45 1.39 1:33 1.41 1.38
Geometric Mean 1.27 1.39 I,33 1.27 1.35 1.31
Coefficient of Variation (%) 37.5 30.2 32.9 37.5 31.0 33.1
_. ..__
--_-.--. -.-- ..- --.-_.^ -.- -- -___ __.- - - _....-
. I,,.a
a 0
Table 6
Summary of Bioavailability (BA) Results: Statistics for PharmacokineticParametersby Treatment and Gender
Per Protocol Intent-to-Treat
Parameter Treatment Statistic Males Females Total Males Females Total
1112
F N 9 10 19 9 10 19
Arithmetic Mean 21.38 19.37 20.32 21.38 19.37 20.32
Geometric Mean 20.71 18.25 19.38 29.71 18.25 19.38
Coefficient of Variation (%) 26.1 38.3 32.0 26.1 38.3 32.0
T N 9 10 19 9 11 20
Arithmetic Mean 18.70 17.48 18.06 18.70 17.20 17.88
Gcomebic Mean 18.18 16.81 17.44 18.18 16.57 17.28
Coefficient of Variation (%) 25.2 29.5 26.9 25.2 28.9 26.8
lambda-z
F N 9 10 19 9 10 19
Arithmetic Mean 0.0346 0.0401 0.0375 0.0346 0.0401 0.0375
Geometric Mean 0.0335 0.0380 0.0358 0.0335 0.0380 0.0358
Coefficient of Variation (%) 27.2 32.4 30.6 27.2 32.4 30.6
T N 9 10 19 9 11 20
Arithmetic Mean 0.0392 0.0429 0.0412 0.0392 0.0434 0.0415
Geometric Mean 0.0381 0.0412 0.0397 0.0381 0.0418 0.0401
Coefficient of Variation (%) 25.2 28.9 27.1 25.2 27.4 26.4
5. DISCUSSION AND CONCLUSIONS
The objectives of this study were to test for bioequivalencebetween the currently-
marketed doxycycline hyclate 20 mg capsuleand a doxycycline hyclate 20 mg tablet; and
- to evaluate possible food effects in the pharmacokinetic profile of doxycycline hyclate 20
mg tablets.
The capsuleand tablet formulations of doxycycline are bioequivalent since the 90%
confidence interval for the ratio of meansfor both AUC and C, fell within 80%- 125%.
The Ieast squaresmean was close to lOO%, which indicates a high level of
bioequivalence.
AUC and C, were higher, and ttn was shorter in females than males. These gender
differences appearto be more marked for the fastelPcapsulecondition compared to the
fasted tablet condition as summarizedin the following Table 7:
-
_-_-.
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; Table 7: Summary of Gender Analysis
Parameter 1 Male(M) Female (F) Comments
AUCo- 4925 ng.h/mL 6025 ng.h/mL F22.30/aM
J
AUCh 5259 ng.hlmL 5700 ng.h/mL F8.4%>M
Gax 243.6 ng/mL 418.1 ng/mL F71.60/aM
C “px 294.1 ng/mL 403.2 ng/mL F37.10/aM
1 Tablet
tIR 18.7 hr 17.5 hr M6.9%>F
Tablet
I I I
Bioavailability Fed AUCh 4568 ng.h/rnL 5359 ng.hlmL F17.3%M
(Food Effect) Tablet -
I I I
Fasted AUCb 5259 ng.h/mL 5700 ng.h/mL F8.4%>M
Tablet
, J
, cmx 225.8 ng/mL 292.6 ng/mL F29.6%>M
Gnan 294.1 ng/mL 403.2 ng/mL F37.1 %>M
I J
tin 21.4 hr 19.4hr M10.3%>F
tlR 18.7 hr 17.5 hr M6.9%>F
1 J __-
LX 3.22 hr 3.55 l-u F10.30/aM
I I I
Lax 1.33 hr 1.45 hr F9.00/o>M
There is a food effect since the 90% lower confidence limit for the ratio of means (fed to
fasted) for ALJC fell below 80% and the 90% lower confidence limit for the ratio of
means (fed to fasted) for C, fell below 70%. The AUC and C, were lower and the
t was higher in the fed state, indicating that food decreases the rate and extent of
aT:orption and delays the time at which maximal concentrations are reached.
Female subjects had a higher AUC and maximum concentration (C,), a Ionger tmu. and
a shorter tin than males. Gender differences in AUC and tl12appear to be more marked
for the fed tablet condition compared to the fasted tablet condition. Conversely, for C-,
_____ . __.._ ..~_ .-..
. __. _---
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a more marked gender difference is seen in the fasted tablet condition compared to the
fed tablet condition (Table 7).
Final Conclusions
The capsule and tablet formulations of doxycycline are bioequivalent since the 90%
confidence interval for the ratio of means for both AUC and C,, fell within 80%-125%.
There is a food effect since the 90% Iower confidence limit for the ratio of means (fed to
fasted) for AUC fell below 80% and the 90% lower confidence limit for the ratio of
means (fed to fasted) for C - fell below 70%. Food decreasesthe rate and extent of
absorption and delays the time at which maxima1 concentrations are reached.
6. COMMENTS:
+ The sponsor discussed differences in pharmacokinetic parameters between males and
females in several places. However, in their demographic distribution table, they did
not report individual or mean weight of the male and fetiale patients. Given that
mean female weight is 1/3ti less than mean male weight, a weight normalized
analysis of the individual pharamcoknietics parameters could have eliminated the
observed differences in pharmacokinetic parameters between male and female
subpopulation and rendered the following comments redundant.
l S In both bioequivalence and food effect bioavailability studies, it was found that AUC
and C, were higher, and tin was shorter in females than males. It is an apparent
anomaly.to the conventional relationship between AUC and tll2 which should be
proportional to each other.
+ Though AUC and Cmax were higher in females than males, the extent of the
difference does not call for recommendation for any dose adjustment.
l 3 Comments pertaining to gender differences in the subheading Gender under Clinical
Pharmacology labeling should be eliminated.
I -. ~...-
-. -_.... .-.- __-_-. ._
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7. LABELING COMMENTS:
Following modifications have been proposedin the “Clinical Pharmacology”
section of the labeling. “W’ means suggesteddeletions and “Shading”
suggestsinsertion of new text.
Pharmacokinetics
The pharmacokinetics of doxycycline following oral administration of Periostat@ were
investigated in 4 volunteer studies involving 107 adults. Additionally, doxycycline
pharmacokinetics have been characterized in numerous scientific publications.2
Pharmacokinetic parametersfor Periostat@ following single oral doses and at steady-state
in healthy subjects are presentedas follows:
t
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/S/
_----_--__-----------
Tapash Ghosh
l/16/01 12:16:40 PM
BIOPHARMACEUTICS
Dennis Bashaw
l/16/01 04:23:25 PM
BIOPHARMACEUTICS
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